Trial Review

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Effectiveness and safety of LM011 in treating subjects diagnosed with non-alcoholic steatohepatitis (NASH).

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Scientific title

An open-label study to assess the efficacy and safety of LM011 in subjects diagnosed with Non-Alcoholic Steatohepatitis (NASH)

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Secondary ID [1]2978180

LM011-18-01

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Universal Trial Number (UTN)

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Trial acronym

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Linked study record

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Health condition

Health condition(s) or problem(s) studied:

Non-Alcoholic Steatohepatitis (NASH)3121850

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Condition category

Condition code

Metabolic and Endocrine31073531073500

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Metabolic disorders

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Oral and Gastrointestinal31082231082200

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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

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Intervention/exposure

Study type

Interventional

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Description of intervention(s) / exposure

LM-011-18-01 is a single arm open label study to test the safety and effectiveness of LM-011 in patients diagnosed with “nonalcoholic steatohepatitis’ (NASH).

20 NASH patients will be enrolled and receive orally LM011 once a day for a duration of 16 weeks. All patients will undergo dose adjustment to reach a desirable target dose following the guidance in the protocol.

Subjects will receive 4 loading doses on Day 1, and one daily maintenance dose starting on Day 2. The loading doses range from 12.5 mL/day to 25 mL/day based on the participant's lean body weight. The initial maintenance dose ranges from 2.5 mL/day to 5 mL/day, also based on the participant's lean body weight.

The therapeutic window of LM011 is narrow with a desired target range of 0.7-1 ng/mL, as such, plasma concentration will be monitored on an ongoing basis. Blood samples will be collected starting at Visits 2, 3, 4, 5 and 6 or at Early Termination. If LM011 plasma concentration is determined to be outside the target range of 0.7 – 1 ng/mL or if clinically significant adverse events related to study drug are reported or significant lean body weight change compared to baseline, the investigator will adjusts the dose according to the guidance of the protocol.

Adherence to the intervention will be monitored in two ways:1. A primary compliance measurement will be calculated based on the volumes provided in Participants’ Dosing Diary. This will be manually entered into the Viedoc EDC system on the Drug Compliance eCRF by the site staff at each visit upon return of the dosing diary by the participant, and will be verified by the CRA during each monitoring visit.

Volume of LM011 Used (mL) will be determined by the Actual Dose Administered (mL) from the participants’ diaries.

Volume of LM011 Expected (mL) will be determined by number of doses expected for the duration between scheduled visits.

2. A secondary check of compliance will be performed through weighing of LM011 bottles prior to dispensing to participants and upon return of LM011 bottles from participants at the next scheduled visit. The weight of the IP bottles before dispensing and upon return of unused and partially used bottles will be entered into the Viedoc EDC system on the Drug Accountability eCRF. The compliance will be programmatically calculated outside of the EDC system and a report will be generated on a weekly basis for CRA review. The CRA will reconcile the primary and secondary compliance values, and follow up with sites where any discrepancies are noted. Participant retraining will be required if inconsistencies are apparent, and further escalation to the CRO and Sponsor will be necessary where inconsistencies are noted more than once. If necessary, such patients will be dropped from the study.

In addition to the monitoring described above, site staff will also reinforce the importance of drug compliance with the patient during scheduled visits as well as during telephone calls with the patients, e.g. when the LM011 concentration results become available, or during general telephone contact calls with the patient as applicable.

MRI-PDFF data will be collected at screening visit and at end-of-study visit (Week 16) for all individual subjects. If there are subjects with missing Week-16 MRI-PDFF data due to drop out, regardless of reasons, two types of analyses will be performed. The first type of analysis will exclude the subject(s) who drop out, while the second type will include the drop-out subject(s) but will assume LM011 has no effect on “liver fat fraction” on these subject(s).

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Timepoint [1]3195850

16 weeks

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Primary outcome [2]3195860

Proportion of subjects with at least a 25% decrease in % steatosis

The percentage change is calculated by taking the difference between the baseline and Week 16 measurements and divide the difference by the baseline value . Similar to that described above for the analysis of the first Primary Endpoint, two types of analysis will also be performed. For subjects drop out early, the first type of analysis will exclude the subject(s) who drop out, while the second type of analysis will include all subject(s) and will assume LM011 had no effect on liver fat fraction on the subjects who drop out early.

At Screening and Week 16, MRI-PDFF over 9 regions of interest will provide estimates of liver fat fractions, measured in %. Based on this biomarker, % steatosis of the liver can be estimated. The percentage change is calculated by taking the difference between the Screening and Week 16 measurements in % steatosis and divide the difference by the Screening % steatosis. Proportion of subjects with at least 25% decrease will be summarized.

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Timepoint [2]3195860

16 weeks

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Secondary outcome [1]3687900

Change in liver fat fraction by MRI-PDFF

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Timepoint [1]3687900

16 weeks or 11 weeks if the subjects early terminated from the study.

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Secondary outcome [2]3687910

Change in aspartate aminotransferase (AST) based on chemistry laboratory test results.AST will be analyzed with a serum assay.

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Timepoint [2]3687910

16 weeks or 11 weeks if the subjects early terminated from the study.

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Secondary outcome [3]3687920

Change in alanine aminotransferase (ALT) based on chemistry laboratory test results.ALT will be analyzed with a serum assay.

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Timepoint [3]3687920

16 weeks or 11 weeks if the subjects early terminated from the study.

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Secondary outcome [4]3687930

Change in enhanced Liver Fibrosis (ELF) Score

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Timepoint [4]3687930

16 weeks or 11 weeks if the subjects early terminated from the study.

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Secondary outcome [5]3687940

Percentage of subjects with at least 15% reduction in liver steatosis

The percentage change is calculated by taking the difference between the baseline and Week 16 measurements and divide the difference by the baseline value. Thus, for conditions with some subjects drop out of study early (hence no measurement on “liver fat fraction” was collected for Week 16), two types of analyses will be conducted: the first analysis will exclude subject(s) who did not complete the study, while the second analysis will include subject(s) who drop out of study early, but will assume LM011 had no effect on liver fat fraction .

At Screening and Week 16, MRI-PDFF over 9 regions of interest will provide estimates of liver fat fractions, measured in %. Based on this biomarker, % steatosis of the liver can be estimated. The percentage change is calculated by taking the difference between the Screening and Week 16 measurements in % steatosis and divide the difference by the Screening % steatosis. Proportion of subjects with at least 15% decrease will be summarized. The calculation is the same as the primary outcome. The only difference is that 15% cutoff is to be used.

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Timepoint [5]3687940

16 weeks or 11 weeks if the subjects early terminated from the study.

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Eligibility

Key inclusion criteria

1. Males or females between 18 and 75 years old with a documented diagnosis of NASH by a licensed medical practitioner within the last 12 months prior to Screening Visit2. BMI between 28 and 40 kg/m2 3. Negative urine drugs-of-abuse screen4. MRI-PDFF at least 15.7%5. Fibroscan score not more than 12 kPa 6. Able and willing to comply with the protocol and availability for all scheduled clinic visits and telephone calls

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Minimum age

18Years

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Maximum age

75Years

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Gender

Both males and females

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Can healthy volunteers participate?

No

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Key exclusion criteria

1. Known cardiovascular disease2. History of cirrhosis based on imaging or clinical criteria and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding.3. History of liver transplantation4. History of hepatocellular carcinoma (HCC)5. History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous carcinoma at the time of Screening visit 6. Females who are pregnant or breastfeeding.7. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (such as systemic corticosteroids, interleukins, interferons).8. Use of any experimental medications within the last 6 months of Screening Visit or during participation of the trial.9. Weight loss of >5% from the time of diagnosis of NASH, based on subject’s reporting10. Currently or participated in a weight loss program within the last 6 months.11. Any history of bariatric surgery.12. Diabetes mellitus Type I13. Daily alcohol intake (on average) >20 ml (2 units)/day for women and 30 ml (3 units)/day for men within the last 12 months prior to Screening Visit and plan to consume the same alcohol amount referenced above during the trial.14. Any severe, acute, or chronic medical or psychiatric condition that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator’s opinion, would make the subject inappropriate for entry into this study.

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Study design

Purpose of the study

Treatment

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Allocation to intervention

Non-randomised trial

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Procedure for enrolling a subject and allocating the treatment (allocation concealment
procedures)

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Methods used to generate the sequence in which subjects will be randomised (sequence
generation)